Biology:IRF8

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene.[1][2][3] IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell.

Function

Interferon Consensus Sequence-binding protein (ICSBP) is a transcription factor of the interferon regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-α and IFN-β. IRF family proteins also control expression of IFN-α and IFN-β-regulated genes that are induced by viral infection.[1]

Knockout studies

IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP knockout (KO) mice, as revealed by lack of CD11clowB220+Ly6C+CD11b− cells. In parallel, CD11c+ cells isolated from ICSBP KO spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP KO mice also displayed a marked reduction of the DC subset expressing the CD8alpha marker (CD8alpha+ DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP-deficient CD8alpha+ DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule ICAM1, CD40, CD80, CD86) and of the T cell area-homing chemokine receptor CCR7.[4]

Clinical significance

In myeloid cells, IRF8 regulates the expression of Bax and Fas to regulate apoptosis.[5] In chronic myelogenous leukemia (CML), IRF8 regulates acid ceramidase to mediate CML apoptosis.[6]

IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation,[7] recent studies, however, have shown that IRF8 is also constitutively expressed in non-hematopoietic cancer cells, albeit at a lower level. Furthermore, IRF8 can also be up-regulated by IFN-γ in non-hemotopoietic cells. IRF8 mediates the expression of Fas, Bax, FLIP, Jak1 and STAT1 to mediate apoptosis in non-hemotopoietic cancer cells.[8][9][10]

Analysis of human cancer genomics database revealed that IRF8 is not significantly focally amplified across the entire dataset of 3131 tumors, but is significantly focally deleted across the entire dataset of 3131 tumors, suggesting that IRF8 is potentially a tumor suppressor in humans.[11] Molecular analysis indicated that the IRF8 gene promoter is hypermethylated in human colon carcinoma cells,[10][12] suggesting that these cells might use DNA methylation to silence IRF8 expression to advance the disease.

Interactions

IRF8 has been shown to interact with IRF1[13][14] and COPS2.[15]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: IRF8 interferon regulatory factor 8". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3394. 
  2. ↑ "Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes". J. Biol. Chem. 267 (35): 25589–96. December 1992. doi:10.1016/S0021-9258(19)74081-2. PMID 1460054. http://www.jbc.org/cgi/reprint/267/35/25589. [yes|permanent dead link|dead link}}]
  3. ↑ "A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein". Mol. Cell. Biol. 22 (11): 3942–57. June 2002. doi:10.1128/MCB.22.11.3942-3957.2002. PMID 11997525. 
  4. ↑ "ICSBP/IRF-8: its regulatory roles in the development of myeloid cells". J. Interferon Cytokine Res. 22 (1): 145–52. January 2002. doi:10.1089/107999002753452755. PMID 11846985. https://zenodo.org/record/1235221. 
  5. ↑ "Cutting edge: IRF8 regulates Bax transcription in vivo in primary myeloid cells". J. Immunol. 187 (9): 4426–30. November 2011. doi:10.4049/jimmunol.1101034. PMID 21949018. 
  6. ↑ "IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia". Cancer Res. 71 (8): 2882–91. April 2011. doi:10.1158/0008-5472.CAN-10-2493. PMID 21487040. 
  7. ↑ "Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene". Cell 87 (2): 307–17. October 1996. doi:10.1016/S0092-8674(00)81348-3. PMID 8861914. 
  8. ↑ "IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression". Cancer Res. 69 (3): 1080–8. February 2009. doi:10.1158/0008-5472.CAN-08-2520. PMID 19155307. 
  9. ↑ "IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression". J. Immunol. 179 (7): 4775–82. October 2007. doi:10.4049/jimmunol.179.7.4775. PMID 17878376. 
  10. ↑ 10.0 10.1 "Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells". Cancer Res. 67 (7): 3301–9. April 2007. doi:10.1158/0008-5472.CAN-06-4068. PMID 17409439. 
  11. ↑ "Tumorscape". The Broad Institute. http://www.broadinstitute.org/tumorscape/pages/portalHome.jsf. 
  12. ↑ "DNA methylation represses IFN-gamma-induced and signal transducer and activator of transcription 1-mediated IFN regulatory factor 8 activation in colon carcinoma cells". Mol. Cancer Res. 6 (12): 1841–51. December 2008. doi:10.1158/1541-7786.MCR-08-0280. PMID 19074829. 
  13. ↑ "Functional domains of interferon regulatory factor I (IRF-1)". Biochem. J. 335 (1): 147–57. October 1998. doi:10.1042/bj3350147. PMID 9742224. 
  14. ↑ "Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors". J. Biol. Chem. 270 (22): 13063–9. June 1995. doi:10.1074/jbc.270.22.13063. PMID 7768900. 
  15. ↑ "Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome". J. Biol. Chem. 275 (50): 39081–9. December 2000. doi:10.1074/jbc.M004900200. PMID 10991940. 

Illustrations

IRF8 in host response.png

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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